Project Summary/Abstract Homeostatic forms of plasticity are thought to have a crucial role in stabilizing neuronal activity in response to changes in excitatory synaptic drive that occur during development, following the induction of Hebbian forms of synaptic plasticity during learning, and in pathological conditions such as sensory impairment, stroke, and other types of neuronal damage. Although much has been learned from studies of homeostatic plasticity in dissociated neuronal cultures, we know relatively little about the mechanisms and properties of homeostatic plasticity at mature synapses in the adult brain. Moreover, computational studies indicate that known forms of homeostatic synaptic plasticity lack important properties needed to both efficiently stabilize neural networks over short time scales and preserve information encoded by differences in the strength of individual synapses. In recent experiments we discovered that decreases in Ca2+ influx via NMDA type glutamate receptors and/or voltage- gated Ca2+ channels induces a novel form of homeostatic potentiation at excitatory synapses onto CA1 pyramidal cells in adult mouse hippocampus. This form of homeostatic potentiation is exceptionally fast and is induced within minutes following a reduction in intracellular Ca2+ levels. Moreover, it may be mediated by the insertion of AMPA type glutamate receptors into silent synapses (i.e. synapses that only contain NMDARs). Thus, it may provide a mechanism that can homeostatically regulate overall excitatory synaptic strength without interfering with changes in synaptic weights induced by Hebbian forms of plasticity, such as long-term depression. However, many fundamental questions regarding the properties and mechanisms involved in this novel form of synaptic plasticity have not yet been investigated. Thus, in this project we propose to use a combination of electrophysiological, pharmacological and biochemical approaches to further characterize this unique form of homeostatic plasticity and begin to identify the underlying cellular and molecular mechanisms.